Materiały źródłowe

• #1 Congenital long QT syndrome: Pathophysiology and genetics – UpToDate

  https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics

  Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD). LQTS may be congenital or acquired. Pathogenic variants in at least 17 LQTS-susceptibility genes have been identified thus far. However, pathogenic variants in the three canonical genes, KCNQ1, KCNH2, and SCN5A, account for at least 75 to 80 percent of all LQTS, with disease-causative variants in the minor LQTS-susceptibility genes contributing only another 5 percent. The pathophysiology and genetics of congenital LQTS will be reviewed here. […] Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications, or QT-prolonging electrolyte disturbances.

• #1 Long QT Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441860/

  The causes of QT interval prolongation can be divided into congenital or acquired. Congenital causes are usually a result of mutations in ion channels (potassium, calcium, or sodium) with more than 15 identified mutations. In contrast, acquired QT interval prolongation may result from electrolyte abnormalities or drugs that affect those ion channels. […] A QT interval duration largely depends on the duration of the ventricular action potential. This duration largely depends on the heart’s closure or opening of ion channels, with the influx of positive ions (sodium, calcium) causing depolarization and the efflux of positive ions (potassium) causing repolarization. Any disturbance in these ion channels that leads to an excess of intracellular positive ions prolongs the action potential, leading to QT prolongation. The pathophysiology of congenital and acquired causes is explained below.

• #1 Molecular pathogenesis of long QT syndrome type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5063268/

  Long QT syndrome type 1 (LQT1) is a subtype of a congenital cardiac syndrome caused by mutation in the KCNQ1 gene, which encodes the -subunit of the slow component of delayed rectifier K+ current (IKs) channel. […] During the past two decades, much advancement has been made in understanding the molecular pathogenesis underlying LQT1. […] The KCNQ1 gene encodes the -subunit of the slow component of delayed rectifier K+ current (IKs) channel (Kv7.1). […] Mutations in KCNQ1 can cause dysfunction in the IKs channel, such as a delay in channel opening or a reduction in the duration for which it is open. […] This results in a decrease in repolarizing K+ current or a loss-of-function during phase 3 of the cardiac AP, which eventually causes QT prolongation and serious arrhythmias. […] A variety of studies have shown that LQT1 is more frequently triggered by adrenergic stimuli (e.g., physical exertion or emotional stress) compared with other forms of LQTS, particularly by diving and swimming.

• #1 Diagnosis, management and therapeutic strategies for congenital long QT syndrome | Heart

  https://heart.bmj.com/content/108/5/332

  In the last 25 years, 17 genes have been associated with LQTS. However, a recent analysis, based on an approach using gene and disease specific metrics designed by the Clinical Genome Resource (ClinGen), reclassified a number of these genes to limited or disputed evidence. […] These remaining genes all encode for ion channels involved in cardiac repolarisation, their modulatory subunits or proteins regulating or modulating the function of ion channels. […] Indeed, specific genotype-phenotype relationships have been described for the three most common subtypes: LQTS types 1, 2 and 3. […] The first two subtypes (LQT1 and 2) are based on functional loss-of-function variants in the potassium channel genes KCNQ1 and KCNH2, respectively. […] These genes respectively encode for the slow and rapid delayed rectifier current I Ks and I Kr, and a smaller amplitude of this current leads to prolongation of the QT interval.

• #1 Genetics of long-QT syndrome | Journal of Human Genetics

  https://www.nature.com/articles/jhg201574

  The LQTS types with dysfunctional late-activating sodium channels (INa) include LQT3, LQT9, LQT10 and LQT12, although most are LQT3. […] A type of LQTS that is associated with a mutation in KCNJ2 is LQT7, which creates a condition known as Andersen-Tawil syndrome. […] The most severe phenotypic form of LQTS is Timothy syndrome (LQT8). […] Numerous ion-channel mutations have been reported and various approaches have been used to confirm the associated functional change, including expression models, experimental mouse models, computational approaches, neonatal mouse cardiomyocytes and induced pluripotent stem cells. […] The goal of identifying the genetic basis of the disease is to individualize and optimize treatment strategies. […] Thus, both genomic and non-genomic factors are important when diagnosing congenital ion-channel diseases and the need to advance genetic analysis is therefore apparent.

• #1 Long QT syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Long_QT_syndrome

  Long QT syndrome is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. […] The common thread linking these variants is that they affect one or more ion currents leading to prolongation of the ventricular action potential, thus lengthening the QT interval. […] The various forms of long QT syndrome, both congenital and acquired, produce abnormal heart rhythms (arrhythmias) by influencing the electrical signals used to coordinate individual heart cells. […] The prolonged action potentials can lead to arrhythmias through several mechanisms. […] The arrhythmia characteristic of long QT syndrome, torsades de pointes, starts when an initial action potential triggers further abnormal action potentials in the form of afterdepolarisations.

• #1 Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | AER Journal

  https://www.aerjournal.com/articles/acquired-long-qt-syndrome-and-electrophysiology-torsade-de-pointes?language_content_entity=en

  Congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval on the surface ECG is a surrogate measure of prolonged ventricular action potential duration (APD). […] Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD, i.e. dispersion of repolarisation (DR). This, together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarisations (EADs), provides the substrate of ventricular tachyarrhythmia (VT) associated with LQTS, usually referred to as torsade de pointes (TdP) VT.

• #1 Long QT syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Long_QT_syndrome

  Early afterdepolarisations, occurring before the cell has fully repolarised, are particularly likely to be seen when action potentials are prolonged, and arise due to reactivation of calcium and sodium channels that would normally switch off until the next heartbeat is due. […] Some research suggests that delayed afterdepolarisations, occurring after repolarisation has completed, may also play a role in long QT syndrome. […] While there is strong evidence that the trigger for torsades de pointes comes from afterdepolarisations, it is less certain what sustains this arrhythmia.

• #1 Long QT Syndrome: Practice Essentials, Background, Etiopathophysiology

  https://emedicine.medscape.com/article/157826-overview

  Long QT syndrome (LQTS) is a congenital disorder characterized by a prolongation of the QT interval on electrocardiograms (ECGs) and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. […] The QT interval represents the duration of activation and recovery of the ventricular myocardium. Prolonged recovery from electrical excitation increases the likelihood of dispersing refractoriness, when some parts of myocardium might be refractory to subsequent depolarization. […] In long QT syndrome (LQTS), TDR increases and creates a functional substrate for transmural reentry. […] In LQTS, QT prolongation can lead to polymorphic ventricular tachycardia, or torsade de pointes, which itself may lead to ventricular fibrillation and sudden cardiac death. Torsade de pointes is widely thought to be triggered by reactivation of calcium channels, reactivation of a delayed sodium current, or a decreased outward potassium current that results in early afterdepolarization (EAD), in a condition with enhanced TDR usually associated with a prolonged QT interval.

• #1 An Overview of Diagnosis and Management Strategies for Long QT Syndrome

  https://www.innovationsincrm.com/cardiac-rhythm-management/articles-2017/june/1046-management-strategies-for-long-qt-syndrome

  Significant clinical, research, genetic, and therapeutic advances in the diagnosis and management of long QT syndrome (LQTS) have made this channelopathy one of the most exciting and enlightening bench-to-bed success stories in the field of cardiology. […] LQTS is a disease of cardiac repolarization characterized by a prolonged QT interval on the ECG, a risk for syncope, seizures, and sudden death. The clinical events are a consequence of the ventricular arrhythmia, torsades de pointes (TdP), that can terminate spontaneously, resulting in syncope, or degenerate into ventricular fibrillation and sudden death. QT prolongation, a consequence of disordered cardiac repolarization, is due to mutations that encode cardiac ion channels or their accessory subunits. […] To date, there are 17 LQTS-susceptible genes that account for approximately 75% to 80% of clinical disease. The majority of patients are affected by the earliest of these identified: mutations in KCNQ1 (long QT syndrome 1; LQT1), KCNH2 (long QT syndrome 2; LQT2), SCN5A (long QT syndrome 3; LQT3). Loss-of-function mutations in KCNQ1-encoded Kv7.1 channels and KCNH2-encoded Kv11.1 channels lead to a decrease in the slowly activating potassium channel (IKs) and rapidly activating potassium channel (IKr), respectively. Normally, because of its fast inactivation (voltage-dependent closing), Nav1.5 does not conduct current (or does so only minimally) during the repolarization phases of the action potential. However, LQT3-linked mutations in SCN5A are gain-of-function mutations that impair the inactivation of Nav1.5, resulting in a late (sustained or persistent) depolarizing Na+ current (late sodium current, INa,L).

• #1 Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness

  https://www.mdpi.com/1422-0067/22/3/1112

  KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its β-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current IKs, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in KCNQ1 result in long QT syndrome, called Romano–Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. […] The present study focuses on the identification of the molecular mechanisms of the KCNQ1 variant, p.P631fs*20 (c.1892_1893insC), leading to rare autosomal recessive LQTS without hearing impairment.

• #1 Genetics of long-QT syndrome | Journal of Human Genetics

  https://www.nature.com/articles/jhg201574

  In 600 patients with LQT1, Moss et al. demonstrated that those with mutations in the transmembrane region of Kv7.1, those with missense mutations and those with mutations resulting in dominant-negative ion currents had greater risk of arrhythmic events than those with other mutations. […] Patients with LQT2 demonstrated that missense mutations in the transmembrane pore region are associated with significantly higher rates of cardiac events than are other missense mutations. […] The LQTS types associated with slowly activating delayed rectifier potassium current (IKs) dysfunction include LQT1, LQT5, LQT11, JLN1 and JLN2, although most are associated with LQT1. […] Mutations in KCNE1, which are associated with LQT5, cause defective trafficking of the IKs channel, reduce amplitude of the IKs current and influence disease pathogenesis.

• #1 Congenital long QT syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-3-18

  The delayed rectifier current (IK) is a major determinant of the phase 3 of the cardiac action potential. It comprises two independent components: one rapid (IKr) and one slow, (IKs). […] The KCNQ1 gene and the KCNE1 gene encode respectively the alpha (KvLQT1) and the (MinK) subunit of the potassium channel conducting the IKs current. KCNQ1 mutations are found in the LQT1 variant of LQTS which is also its most prevalent form. […] The KCNH2 gene and the KCNE2 gene encode respectively the alpha (HERG Human Ether-a-go-go Related Gene) and the (MIRP) subunit of the potassium channel conducting the IKr current. This is the second most common variant of LQTS accounting for 35-40% of mutations in LQTS genotyped patients. […] The SCN5A gene encodes the protein of the cardiac sodium channel. The Na+ channel protein is a relatively large molecule that folds onto itself to surround the channel pore.

• #1

  https://omim.org/entry/613688

  Itzhaki et al. (2011) reported the development of a patient/disease-specific human induced pluripotent stem cell (iPSC) line from a patient with long QT syndrome-2 that was due to an A614V missense mutation in the KCNH2 gene (152427.0026). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes when compared to healthy control cells. Voltage-clamp studies confirmed that this action potential duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. Itzhaki et al. (2011) then used the LQTS human iPSC-derived cardiac tissue model to evaluate the potency of existing and novel pharmacologic agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers, and late sodium-channel blockers) the disease phenotype. Itzhaki et al. (2011) concluded that their study illustrated the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents.

• #1 Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation

  https://www.mdpi.com/1422-0067/22/15/8090

  Many drugs with no structural similarities (antihistamines, antipsychotics, antibiotics) share a common mechanism by which they cause diLQTS and TdP. This shared mechanism has been identified as blockade of the IKr on the cardiac action potential carried out by a voltage-gated potassium channel called Kv11.1. […] The Kv11.1 channel is a homotetramer, composed of four α-subunits all encoded by the same gene (KCNH2). […] The gating kinetics in the different states of the potassium channel have been extensively studied, indicating that Kv11.1 elicits unusual gating kinetics compared to other voltage-gated potassium channels, in that inactivation occurs at a faster rate than activation and deactivation, and is a voltage-dependent process. […] This pharmacological disruption of cardiac repolarization is widely simulated to predict drug proarrhythmic risk in preclinical stages of drug development, mainly using the ICH guidelines.

• #1 The long QT syndrome family of cardiac ion channelopathies: A HuGE review | Genetics in Medicine

  https://www.nature.com/articles/gim200626

  The net effect of LQT1 mutations is a decreased outward K+ current during the plateau phase of the cardiac action potential, i.e., a loss-of-function of the ion channel. The channel remains open longer, ventricular repolarization is delayed, and the QT interval is lengthened. […] Mutations can result in either structural ion channel defects having dominant-negative effects or intracellular trafficking abnormalities causing a reduction in the number of functional ion channels, both leading to loss-of-function. In terms of electrophysiology, HERG mutations cause potassium ion channels to deactivate (close) much faster, blunting the normal rise in current (IKr) that results from rapid recovery from channel inactivation/slow deactivation. The IKr current during the plateau phase is reduced and ventricular repolarization delayed, leading to QT interval prolongation.

• #1

  https://omim.org/entry/613688

  In a surrogate model of LQT2, Akar et al. (2002) investigated a mechanism by which dysfunction at the molecular level may provide the electrical substrate for the life-threatening arrhythmia torsade de pointes. The authors used the novel approach of transmural optical imaging in a canine wedge preparation to determine the spatial organization of repolarization and arrhythmogenesis. They demonstrated islands of midmyocardial cells (M cells) with increased refractoriness, producing steep spatial gradients of repolarization that were directly responsible for conduction block and self-sustained intramural reentrant circuits. These data highlighted a central role for M cells in the development of reentrant torsade de pointes in LQT2. […] Roden and Viswanathan (2005) reviewed the genetics of acquired long QT syndrome and discussed the structural features of the HERG channel that render it more vulnerable to blockade by drugs: the presence of multiple aromatic residues oriented to face the permeation pore, which provide high-affinity binding sites for a wide range of compounds; and the absence of a pair of proline residues in the S6 helix that forms part of the pore, resulting in an unkinked S6 helix in the HERG channel that is hypothesized to increase access to the binding site.

• #1

  https://www.jci.org/articles/view/19844

  In the case of LQT-3 syndrome, however, defects in the Na+ channel were linked to delay in ventricular repolarization (prolongation of the QT interval). […] These initial experiments clearly showed a novel mechanism that could explain this unexpected result: the inherited mutation disrupted the inactivation process of the channel such that, during the plateau phase of the action potential, a small number of Na+ channels do not inactivate (become nonconducting) but in fact reopen to provide a very small depolarizing current. […] Thus, the molecular genetic analysis of LQTS patients has led to a novel understanding of the importance of Na+ channel activity in controlling not only the QRS complex, but also the duration of the ventricular electrical response: the QT interval. […] Investigation of the molecular basis of LQTS has led to fundamental insight into the molecular identity of key K+ channel subunits in the heart, notably the two key delayed rectifier currents IKr and IKs, which have been demonstrated in animal models to be crucial to control of cardiac action potential duration.

• #1

  https://link.springer.com/article/10.1007/s00246-019-02151-x

  The presence of a mutation in the C-loop structure confers the highest risk for aborted cardiac arrest or sudden death. […] The gain-of-function mutations of SCN5A disrupt the fast inactivation of the cardiac sodium channels and are associated with LQT3 phenotype, accounting for 5-10% of total LQTS cases. […] LQT3 may manifest on the surface electrocardiogram as a prolonged isoelectric interval preceding a relatively normal T-wave morphology. […] Jervell and Lange-Nielsen syndrome (JLNS), a relatively rare form of LQTS, is an autosomal recessive disorder associated with congenital profound sensorineural hearing loss and usually marked QTc prolongation. […] An additional six rare forms of LQTS involve ion channels: KCNE1 (LQT5), KCNE2 (LQT6), KCNJ2 (LQT7), CACNA1 (LQT8), SCN4B (LQT10), and KCNJ5 (LQT13).

• #1 An Overview of Diagnosis and Management Strategies for Long QT Syndrome

  https://www.innovationsincrm.com/cardiac-rhythm-management/articles-2017/june/1046-management-strategies-for-long-qt-syndrome

  The severe arrhythmia phenotypes noted in the fetal state can be explained in part by mutations with severe biophysical phenotypes. […] The net effect of sex hormones on the expression and function of cardiac ion channels is thought to be a lower repolarization reserve in women, rendering them more prone to QTc prolongation and TdP occurrence in the presence of a LQTS-causing mutation. […] LQT1 patients are particularly vulnerable to life-threatening events during exertion, and are most responsive to β-blockers. […] LQT2 is known to be life-threatening in females of child-bearing age when compared with male counterparts of the same age. […] LQT3 events occur during times of relative bradycardia and thus may manifest during sleep. […] In high-risk patients in whom β-blockers are either not effective or not tolerated, or are used in patients who are non-compliant, there should be a strong consideration for LCSD.

• #1 Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | AER Journal

  https://www.aerjournal.com/articles/acquired-long-qt-syndrome-and-electrophysiology-torsade-de-pointes?language_content_entity=en

  Acquired LQTS is by far, more prevalent than congenital LQTS. The vast majority of acquired LQTS is the result of the adverse effect of drugs and/or electrolyte abnormalities, which, in the majority of cases, interact with the human ether- -go-go-related gene (hERG) encoding the pore-forming subunits (Kv11.1) of the rapidly activating delayed rectifier current, IKr. However, recent reports suggest that some drugs can also increase the late sodium current, which may contribute to their proarrhythmic effect. […] The vast majority of acquired LQTS is the result of adverse effects of drugs that interact with the hERG gene, and the IKr. However, although most drugs that cause TdP do so via hERG channel blockade, TdP is not necessarily a potential consequence of all drugs blocking the hERG pathway.

• #1 Long QT syndrome – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/long-qt-syndrome/symptoms-causes/syc-20352518

  Acquired long QT syndrome. This type of LQTS is caused by another health condition or medicine. It usually can be reversed when the specific cause is found and treated. […] Many genes and gene changes have been linked to long QT syndrome (LQTS). […] A medicine or other health condition can cause acquired long QT syndrome. […] If a medicine causes acquired long QT syndrome, the disorder may be called drug-induced long QT syndrome. More than 100 medicines can cause prolonged QT intervals in otherwise healthy people. […] Health conditions that can cause acquired long QT syndrome include: […] Proper medical treatment and lifestyle changes can help prevent complications of long QT syndrome.

• #1 Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation

  https://www.mdpi.com/1422-0067/22/15/8090

  The most common cause of aLQTS is attributed to the use of certain drugs widely used within the clinical setting such as antihistamines, antibiotics, antidepressants, and prokinetics. […] The risk of diLQTS is largely determined by the drug’s interaction with a variety of cardiac ion channels. Thus, variants in the genes encoding cardiac ion channel subunits can modify the drug-channel interaction, increasing its binding affinity or its gating kinetics. […] The aim of this article is to highlight the molecular and genetic aspects of aLQTS, given that diLQTS represents an unacceptable risk of sudden death in patients receiving treatment for non-life-threatening conditions. […] The proposed mechanism whereby drugs produce prolongation of the QT interval is through inhibition of the outward rapid delayed rectifier potassium current (IKr), which prolongs individual cardiac ventricular action potentials. This renders individual cardiac cells susceptible to develop EADs, which are the substrate for developing TdP, via phase 2 reentry.

• #1 Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | AER Journal

  https://www.aerjournal.com/articles/acquired-long-qt-syndrome-and-electrophysiology-torsade-de-pointes?language_content_entity=en

  Recent studies have shown that some drugs designated as arrhythmogenic IKr blocker can generate arrhythmias by augmenting INa-L through the PI3K pathway. […] Several recent reports from this laboratory have provided strong evidence for a pathogenic role of autoimmune and inflammatory conditions in the development of QTc prolongation. […] In summary, cardiac or systemic inflammation promotes QTc-interval prolongation via cytokine-mediated effects and this may increase SCD risk. […] The susceptibility to acquired QT interval prolongation can be influenced by genetic variations. […] The overall incidence of drug-induced LQTS in a given population is difficult to estimate. […] QT prolongation is one of the most common reasons for drug withdrawal from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient.

• #1 Long QT Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441860/

  Mutation in genes coding for ion channel proteins results in their malfunction, leading to excess intracellular positivity. Though rare, this entity results in a high risk of sudden death. So far, mutations of any of 15 genes have been linked to Long QT syndrome, with KCNQ1 being the most common gene mutated and is the cause of Long QT syndrome type 1. […] More commonly, prolongation of QT interval is acquired. As one can expect, disturbances of electrolytes (hypokalemia, hypocalcemia, hypomagnesemia) prolong QT. Also, certain medications affect those ion channels and lead to QT prolongation. Virtually all drugs that produce Long QT syndrome act by blocking the outward IKr current, which is mediated by the potassium channel encoded by the KCNH2 gene.

• #1 An Overview of Diagnosis and Management Strategies for Long QT Syndrome

  https://www.innovationsincrm.com/cardiac-rhythm-management/articles-2017/june/1046-management-strategies-for-long-qt-syndrome

  Genetic testing in LQTS has allowed for the development of a better understanding of the phenotype-genotype correlations. […] The onset of TdP differs among LQTS genotypes. In LQT1, TdP usually occurs at fast heart rates, while in LQT2 it is often preceded by a pause, and the R-R interval immediately before TdP is significantly longer in LQT2 than in LQT1 patients. […] Fever, medications, and electrolyte levels factor into disease expression. […] Hypokalemia is an independent risk factor contributing to reduced survival of cardiac patients and increased incidence of arrhythmic death. […] Medications have long been associated with arrhythmic events in LQTS patients, unmasking the disease in some and contributing to sudden death in others. […] Patient age and sex modify the QT interval and disease expression.

• #1 Long QT Interval Syndromes – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/arrhythmogenic-cardiac-disorders/long-qt-interval-syndromes

  Prolongation of action potentials increases the probability of transmembrane voltage oscillations occurring during the depolarized myocyte action potential (early afterdepolarizations). If the action potential durations of myocytes in a local area vary, these oscillations may reactivate neighboring myocytes that have repolarized and thus create torsades de pointes ventricular tachycardia (TdeP VT). The risk of TdeP VT is dependent on the degree of QTc prolongation, particularly if it is 0.50 second. […] LQTS (particularly LQTS3) may also cause paroxysmal atrial fibrillation. […] The occurrence of TdeP VT is favored by any condition that further prolongs action potential duration, including female sex, bradycardia, hypokalemia, hypomagnesemia, and hypothyroidism. […] Long QT interval syndromes are classified based on the specific gene that has mutated.

• #1

  https://link.springer.com/article/10.1007/s12012-024-09853-6

  Long QT syndrome (LQTS) is a heterogeneous group of disorders caused by cardiac repolarization maladaptation. This dysfunction is characterized by a prolonged QT interval on electrocardiographic (ECG) readings and is associated with an increased risk of adverse cardiac events, such as tip-twisting ventricular tachycardia (TdP), recurrent syncope, cardiac arrest, and potentially sudden death. LQTS can be classified as hereditary or acquired. Acquired LQTS (aLQTS) occur in approximately 0.7% of hospitalized patients and are often linked to underlying medical conditions or the use of certain medications. […] The pathogenic of aLQTS are mainly external factors. Common causes include electrolyte disturbances such as hypokalemia, congestive heart failure, coronary heart disease, diabetes mellitus, myocardial ischemia, and some QT-prolonging medications. These factors often lead to functional alterations in various potassium and calcium channels, such as Kv11.1 potassium selective channels encoded by human cardiac Ether- -go-gorelated gene (hERG), potassium voltage-gated channel subfamily Q member 1, ATP-sensitive potassium channels, Kir3.1 potassium channels, transient outward potassium channels and Long-lasting calcium channel (L-CaV). Among these causes, drugs play a significant role in triggering aLQTS. Known drugs that can cause LQTS include antiarrhythmics, antineoplastics, antidepressants, nonsteroidal analgesics, and opioid analgesics, among others.

• #1 Another Potential Mechanism for Long QT Intervalslogo-32logo-40logo-60NEJM Journal WatchnejmJW_1L_RGB-b

  https://www.jwatch.org/na52736/2020/11/04/another-potential-mechanism-long-qt-intervals

  Intense exercise may be a cause of reversible long QT interval. […] A prolonged QT interval can be seen in people with congenital long QT syndromes or with people using medications that affect the ion channels involved in long QT syndromes. […] After deconditioning, the mean QTc shortened from 492 milliseconds to 423 milliseconds. […] This intriguing study from Italy provides relatively convincing evidence that intense training could reversibly increase the QT interval in some individuals. […] I suspect that they would likely also show a pronounced QT lengthening with drugs that affect repolarization channels.

• #1 Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | AER Journal

  https://www.aerjournal.com/articles/acquired-long-qt-syndrome-and-electrophysiology-torsade-de-pointes?language_content_entity=en

  In the past decade, hERG channel-mediated cardiac toxicity, manifested as QT interval prolongation, has become a major safety issue in drug development, superseding liver injury as the main cause of drug withdrawals. […] The electrophysiological mechanisms of the trigger of Torsade de Pointes in the Long QT Syndrome suggest that a spontaneous release of calcium from the sarcoplasmic reticulum would temporarily increase cytosolic calcium concentration with a subsequent sudden activation of the sodium-calcium exchanger inward current. […] The ionic mechanism(s) that underlie the generation of EADs have been widely investigated. […] The electrophysiological mechanisms of self-terminating versus non-self-terminating Torsade de Pointes Ventricular Tachyarrhythmia have never been elucidated.

• #1 Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | AER Journal

  https://www.aerjournal.com/articles/acquired-long-qt-syndrome-and-electrophysiology-torsade-de-pointes

  In the past decade, hERG channel-mediated cardiac toxicity, manifested as QT interval prolongation, has become a major safety issue in drug development, superseding liver injury as the main cause of drug withdrawals. […] The electrophysiological mechanisms of the trigger of Torsade de Pointes in the Long QT Syndrome suggest that a spontaneous release of calcium from the sarcoplasmic reticulum would temporarily increase cytosolic calcium concentration with a subsequent sudden activation of the sodium-calcium exchanger inward current. […] The ionic mechanism(s) that underlie the generation of EADs have been widely investigated. […] The electrophysiological mechanism of VT in LQTS is somewhat more complex than that described earlier. […] The majority of TdP episodes terminate spontaneously (self-terminating), however, a minority can degenerate in VF (non-self-terminating).

• #1 Diagnosis, management and therapeutic strategies for congenital long QT syndrome | Heart

  https://heart.bmj.com/content/108/5/332

  Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. […] Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype-phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. […] The various milestones in the over 60 years history of this disease are nicely summarised in a recent personal review by Dr Schwartz.

• #1 Molecular pathogenesis of long QT syndrome type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5063268/

  When IKs is defective because of a KCNQ1 mutation, the ventricular repolarization or QT interval fails to shorten appropriately, thus creating a highly arrhythmogenic condition. […] The LQT1-related KCNQ1 gene is 404 kb long and located on chromosome 11p15.5. […] To date, over 250 mutations in KCNQ1 have been found to be linked to LQT1 and new LQT1 causing mutations continue to be identified. […] Importantly, these data are consistent with the results from another clinical study. […] Mutations in the transmembrane, linker, and pore region of KCNQ1 are usually defined as high-probability disease-causing mutations that tend to cause severe cardiac events in patients at younger ages compared to mutations in the COOH terminal region. […] The mutation type, specific location, and degree of dysfunction play a critical role in the clinical course of LQT1.

• #1 Diagnosis, management and therapeutic strategies for congenital long QT syndrome | Heart

  https://heart.bmj.com/content/108/5/332

  For example, comorbidities like hypertension may aggravate the LQTS phenotype by deleterious effects of the interaction between hypertrophy and the mutation. […] Furthermore, recent data show evidence for a more complex polygenic architecture in genotype-negative patients, and preliminary evidence in single families has revealed evidence for the existence of both protective as well as deleterious alleles, which may modify the phenotype by, respectively, aggravating or alleviating the QT-prolonging effects of a LQTS-causing mutation. […] In summary, congenital LQTS is an inheritable entity characterised by a prolonged heart-rate corrected QT interval, and it associates with malignant arrhythmias at young age. It is caused by a decrease in repolarising cardiac ion currents in a complex polygenic composition and interacting with multiple other factors such as sex, age, comorbidities and triggers such as drugs.

• #1 Diagnosis, management and therapeutic strategies for congenital long QT syndrome | Heart

  https://heart.bmj.com/content/108/5/332

  LQTS type 3 is based on gain-of-function variants in SCN5A, the gene encoding the fast inward cardiac sodium current (I Na). […] Gain of function relates to an increased amplitude of the late sodium inward current (during the plateau phase), which will also lead to prolongation of the action potential. […] The age of onset of arrhythmias is typically younger in LQT1 patients and in particular LQT1 males are at risk, whereas most LQT2 and LQT3 patients who become symptomatic experience their first symptoms around puberty and here particular females are at risk. […] The arrhythmias in LQTS originate from the last part of the ventricular action potential where severe action potential prolongation results in early afterdepolarisations that at one instant reach threshold for subsequent fast sodium inward current and a trigger beat that then degenerates into fast polymorphic ventricular arrhythmia: Torsades de Pointes and ventricular fibrillation.

• #1

  https://www.jci.org/articles/view/19844

  Together, these findings motivated investigation into molecular links between the SNS and regulation of KCNQ1/KCNE1 channels in the human heart. […] When the KCNQ1/KCNE1 complex is disrupted by an inherited mutation, an unbalanced cellular response occurs, which leads to dysfunctional rhythm. […] The discovery that distinct LQTS variants were associated with genes coding for different ion channel subunits has had a major impact on the diagnosis and analysis of LQTS patients. […] The greatest difference in risk factors becomes apparent in comparing LQT-3 syndrome patients (SCN5A mutations) and patients with LQT-1 syndrome (KCNQ1 mutations) or LQT-2 syndrome (HERG mutations). […] One of the major contributions of the integration of cellular, molecular, and genetic techniques in the investigation of the causes and treatment of congenital LQTS has been the emergence of mutation-specific strategies for disease therapy.

• #1

  https://link.springer.com/article/10.1007/s00246-019-02151-x

  Other very rare LQTS variants are related to kinase activities, such as AKAP9 (LQT11), CALM1 (LQT14), and CALM2 (LQT15). […] The ECG of a patient with LQTS characteristically shows QT prolongation when measured appropriately in leads II or V5 using a correction formula for heart rate (QTc). […] QTc values correlate with risk of life-threatening arrhythmia event with a linear relationship between increasing QTc and increasing risk for all three common genotypes, LQT1, 2, and 3. […] The current standard of care therapy for LQT1, 2, and 3 includes non-cardioselective beta-blockers, preferentially nadolol, that are hypothesized to dampen down adrenergic stimulation of the heart. […] Beta-blockers are proven to reduce the occurrence of life-threatening ventricular arrhythmias and subsequent risk of sudden death in LQTS patients.

• #1 Reddit – The heart of the internet

  https://www.reddit.com/r/Step2/comments/120ho8i/through_what_mechanism_are_betablockers/

  In addition, beta blockers (class II antiarrhythmics) dampen sympathetic activity and shorten the QT interval at rapid heart rates to reduce the risk of syncope and death in patients with congenital LQTS. […] I understand per the Bazeet correction that it reduces the QTc, but it doesn’t make intuitive sense.

• #1

  https://www.jci.org/articles/view/19844

  Because the functional consequences of most of the Na+ channel mutations that cause LQT-3 syndrome are subtle increases in channel activity during the action potential plateau, cellular experimental work suggested that conventional Na+ channel blockers such as mexiletine, tocainide, and lidocaine might prove useful in treating this LQTS variant. […] Thus genotype, which underlies phenotype, can dictate the most promising therapeutic approach.

• #1

  https://link.springer.com/article/10.1007/s00246-019-02151-x

  Recently, the application of a drug developed to assist with ion channel trafficking to the cell membrane in cystic fibrosis has shown promise for rescuing the phenotype of LQTS in patients with trafficking defects in hERG. […] Given the gain-of-function mutation in LQT3, it is mechanistically intuitive that sodium channel blockade would ameliorate risk of arrhythmia. […] CRISPR/Cas9 is a highly accurate and efficient genome editing technique, which is faster and cheaper than other preceding gene editing technologies. […] CRISPR/Cas9 can generate isogenic mutant lines from control iPSCs, or genetically corrected iPSCs from mutant lines, thus eliminating epigenetic differences or unknown genetic modifiers which may introduce phenotype variability in studying disease-causing mutations in LQTS.

• #1

  https://link.springer.com/article/10.1007/s00246-019-02151-x

  RNA interference (RNAi)-based therapeutics may prove an effective adjunct to standard of care therapy in LQTS. […] Studies have demonstrated the potential RNAi offers for the treatment of LQTS and its ability to be patient-specific in cultured cells. […] LQTS is a rare inherited cardiac condition associated with risk of malignant ventricular arrhythmias. […] The three major subtypes of LQTS are LQT1, LQT2, and LQT3, caused by mutations in the ion channel genes KCNQ1, KCNH2, and SCN5A, respectively. […] Current standard of care therapy for LQTS is the prescription of non-cardioselective beta-blockers. […] Increasingly, a more nuanced understanding of LQTS pathophysiology is leading towards genotype-specific therapies such as the role of mexiletine for a subset of patients with LQT3.

• #1 The long QT syndrome family of cardiac ion channelopathies: A HuGE review | Genetics in Medicine

  https://www.nature.com/articles/gim200626

  LQT3 mutations lead to the reopening of sodium channels (i.e., gain-of-function), thereby enhancing the inward plateau current and prolonging repolarization. […] The effect of a given mutation can be potentiated when existing in combination with a second mutation in a separate LQTS locus (e.g., the mild SCN5A A572D mutation coexisting with a more serious KCNQ1 V254M mutation). […] QT prolongation associated with heart failure is a common, acquired form of the syndrome.

• #1 Molecular pathogenesis of long QT syndrome type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5063268/

  The findings to date indicate that mechanisms underlying LQTS are not only multifactorial, but are also involved in pathway crosstalk. […] The loss-of-function in IKs, which is a major repolarization current, occurs due to a KCNQ1 mutation and decreases the repolarization reserve. […] However, this may be insufficient to elicit a full-blown LQT1 phenotype, especially at rest.

• #1 Clinical and Genetic Characteristics of Long QT Syndrome – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-clinical-and-genetic-characteristics-of–articulo-13109918

  Long QT syndrome (LQTS) is an arrhythmogenic ion channel disorder characterized by severely abnormal ventricular repolarization, which results in prolongation of the electrocardiographic QT interval. […] Eleven years after the identification of the principle cardiac channels involved in the condition, hundreds of mutations in, to date, 10 genes have been associated with the syndrome. […] Genetic investigations carried out up until the present have shown that, although the severe form of the disease is sporadic, there are a number of common polymorphisms in genes associated with the condition that may confer susceptibility to the development of torsade de pointes in some individuals, particularly when specific drugs are being administered. […] Understanding of the molecular processes underlying the syndrome has enabled treatment to be optimized and has led to better survival among sufferers, thereby demonstrating a key correspondence between genotype, phenotype and therapy.

• #2 Long QT syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Long_QT_syndrome

  Long QT syndrome is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. […] The common thread linking these variants is that they affect one or more ion currents leading to prolongation of the ventricular action potential, thus lengthening the QT interval. […] The various forms of long QT syndrome, both congenital and acquired, produce abnormal heart rhythms (arrhythmias) by influencing the electrical signals used to coordinate individual heart cells. […] The prolonged action potentials can lead to arrhythmias through several mechanisms. […] The arrhythmia characteristic of long QT syndrome, torsades de pointes, starts when an initial action potential triggers further abnormal action potentials in the form of afterdepolarisations.

• #2 Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | AER Journal

  https://www.aerjournal.com/articles/acquired-long-qt-syndrome-and-electrophysiology-torsade-de-pointes?language_content_entity=en

  Congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval on the surface ECG is a surrogate measure of prolonged ventricular action potential duration (APD). […] Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD, i.e. dispersion of repolarisation (DR). This, together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarisations (EADs), provides the substrate of ventricular tachyarrhythmia (VT) associated with LQTS, usually referred to as torsade de pointes (TdP) VT.

• #2 Long QT Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441860/

  Mutation in genes coding for ion channel proteins results in their malfunction, leading to excess intracellular positivity. Though rare, this entity results in a high risk of sudden death. So far, mutations of any of 15 genes have been linked to Long QT syndrome, with KCNQ1 being the most common gene mutated and is the cause of Long QT syndrome type 1. […] More commonly, prolongation of QT interval is acquired. As one can expect, disturbances of electrolytes (hypokalemia, hypocalcemia, hypomagnesemia) prolong QT. Also, certain medications affect those ion channels and lead to QT prolongation. Virtually all drugs that produce Long QT syndrome act by blocking the outward IKr current, which is mediated by the potassium channel encoded by the KCNH2 gene.

• #2 An Overview of Diagnosis and Management Strategies for Long QT Syndrome

  https://www.innovationsincrm.com/cardiac-rhythm-management/articles-2017/june/1046-management-strategies-for-long-qt-syndrome

  Significant clinical, research, genetic, and therapeutic advances in the diagnosis and management of long QT syndrome (LQTS) have made this channelopathy one of the most exciting and enlightening bench-to-bed success stories in the field of cardiology. […] LQTS is a disease of cardiac repolarization characterized by a prolonged QT interval on the ECG, a risk for syncope, seizures, and sudden death. The clinical events are a consequence of the ventricular arrhythmia, torsades de pointes (TdP), that can terminate spontaneously, resulting in syncope, or degenerate into ventricular fibrillation and sudden death. QT prolongation, a consequence of disordered cardiac repolarization, is due to mutations that encode cardiac ion channels or their accessory subunits. […] To date, there are 17 LQTS-susceptible genes that account for approximately 75% to 80% of clinical disease. The majority of patients are affected by the earliest of these identified: mutations in KCNQ1 (long QT syndrome 1; LQT1), KCNH2 (long QT syndrome 2; LQT2), SCN5A (long QT syndrome 3; LQT3). Loss-of-function mutations in KCNQ1-encoded Kv7.1 channels and KCNH2-encoded Kv11.1 channels lead to a decrease in the slowly activating potassium channel (IKs) and rapidly activating potassium channel (IKr), respectively. Normally, because of its fast inactivation (voltage-dependent closing), Nav1.5 does not conduct current (or does so only minimally) during the repolarization phases of the action potential. However, LQT3-linked mutations in SCN5A are gain-of-function mutations that impair the inactivation of Nav1.5, resulting in a late (sustained or persistent) depolarizing Na+ current (late sodium current, INa,L).

• #2 Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | AER Journal

  https://www.aerjournal.com/articles/acquired-long-qt-syndrome-and-electrophysiology-torsade-de-pointes?language_content_entity=en

  Acquired LQTS is by far, more prevalent than congenital LQTS. The vast majority of acquired LQTS is the result of the adverse effect of drugs and/or electrolyte abnormalities, which, in the majority of cases, interact with the human ether- -go-go-related gene (hERG) encoding the pore-forming subunits (Kv11.1) of the rapidly activating delayed rectifier current, IKr. However, recent reports suggest that some drugs can also increase the late sodium current, which may contribute to their proarrhythmic effect. […] The vast majority of acquired LQTS is the result of adverse effects of drugs that interact with the hERG gene, and the IKr. However, although most drugs that cause TdP do so via hERG channel blockade, TdP is not necessarily a potential consequence of all drugs blocking the hERG pathway.

• #2 Diagnosis, management and therapeutic strategies for congenital long QT syndrome | Heart

  https://heart.bmj.com/content/108/5/332

  In the last 25 years, 17 genes have been associated with LQTS. However, a recent analysis, based on an approach using gene and disease specific metrics designed by the Clinical Genome Resource (ClinGen), reclassified a number of these genes to limited or disputed evidence. […] These remaining genes all encode for ion channels involved in cardiac repolarisation, their modulatory subunits or proteins regulating or modulating the function of ion channels. […] Indeed, specific genotype-phenotype relationships have been described for the three most common subtypes: LQTS types 1, 2 and 3. […] The first two subtypes (LQT1 and 2) are based on functional loss-of-function variants in the potassium channel genes KCNQ1 and KCNH2, respectively. […] These genes respectively encode for the slow and rapid delayed rectifier current I Ks and I Kr, and a smaller amplitude of this current leads to prolongation of the QT interval.

• #2 Long QT Interval Syndromes – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/arrhythmogenic-cardiac-disorders/long-qt-interval-syndromes

  More than 15 forms of LQTS have been described, but most cases fall into 3 subgroups: […] Long QT syndrome type 1 (LQTS1): Loss-of-function mutation of gene KCNQ1, which encodes an adrenergic-sensitive Kv7.1 channel responsible for the slow outward potassium current (IKs). […] Long QT syndrome type 2 (LQTS2): Loss-of-function mutation of gene KCNH2, which encodes the hERG channel responsible for the rapid outward potassium current (IKr). […] Long QT syndrome type 3 (LQTS3): Gain-of-function mutation of gene SCN5A, which encodes the Nav1.5 channel responsible for the inward sodium current (INa). […] The vast majority of cases are LQTS1, LQTS2, or LQTS3. These 3 forms are inherited as autosomal dominant disorders with incomplete penetrance. […] Some forms of LQTS are more associated with certain triggers than others.

• #2

  https://omim.org/entry/613688

  In a surrogate model of LQT2, Akar et al. (2002) investigated a mechanism by which dysfunction at the molecular level may provide the electrical substrate for the life-threatening arrhythmia torsade de pointes. The authors used the novel approach of transmural optical imaging in a canine wedge preparation to determine the spatial organization of repolarization and arrhythmogenesis. They demonstrated islands of midmyocardial cells (M cells) with increased refractoriness, producing steep spatial gradients of repolarization that were directly responsible for conduction block and self-sustained intramural reentrant circuits. These data highlighted a central role for M cells in the development of reentrant torsade de pointes in LQT2. […] Roden and Viswanathan (2005) reviewed the genetics of acquired long QT syndrome and discussed the structural features of the HERG channel that render it more vulnerable to blockade by drugs: the presence of multiple aromatic residues oriented to face the permeation pore, which provide high-affinity binding sites for a wide range of compounds; and the absence of a pair of proline residues in the S6 helix that forms part of the pore, resulting in an unkinked S6 helix in the HERG channel that is hypothesized to increase access to the binding site.

• #2 Long QT syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Long_QT_syndrome

  Early afterdepolarisations, occurring before the cell has fully repolarised, are particularly likely to be seen when action potentials are prolonged, and arise due to reactivation of calcium and sodium channels that would normally switch off until the next heartbeat is due. […] Some research suggests that delayed afterdepolarisations, occurring after repolarisation has completed, may also play a role in long QT syndrome. […] While there is strong evidence that the trigger for torsades de pointes comes from afterdepolarisations, it is less certain what sustains this arrhythmia.

• #2 Long QT Syndrome (LQTS)

  https://www.utmb.edu/pedi_ed/CoreV2/Cardiology/cardiologyV2/cardiologyV217.html

  Long QT syndrome may be caused by an imbalance of the sympathetic innervation in the heart especially the stellate ganglion or derangements in the cardiac ion flow, resulting in prolongation of the action potential. During the latter phase of the action potential, the myocardium is very excitable and may develop arrhythmia if stimulated electrically or mechanically. If a PVC occurs during this phase of the action potential (R on T phenomenon), a delayed after-depolarization develops in the form of a specific polymorphic ventricular arrhythmia (Torsades de pointes) […] Long QT syndrome may be caused by an imbalance of the sympathetic innervation in the heart especially the stellate ganglion or derangements in the cardiac ion flow, resulting in prolongation of the action potential. During the latter phase of the action potential, the myocardium is very excitable and may develop arrhythmia if stimulated electrically or mechanically. If a PVC occurs during this phase of the action potential (R on T phenomenon), a delayed after-depolarization develops in the form of a specific polymorphic ventricular arrhythmia (Torsades de pointes) […] LQTS is a serious condition and the risk factors for sudden death include long QT 0.55 seconds, family history of sudden death, bradycardia for age, and a prior history of symptoms. Any medications that may cause QT prolongation should be discontinued.

• #2 Diagnosis, management and therapeutic strategies for congenital long QT syndrome | Heart

  https://heart.bmj.com/content/108/5/332

  LQTS type 3 is based on gain-of-function variants in SCN5A, the gene encoding the fast inward cardiac sodium current (I Na). […] Gain of function relates to an increased amplitude of the late sodium inward current (during the plateau phase), which will also lead to prolongation of the action potential. […] The age of onset of arrhythmias is typically younger in LQT1 patients and in particular LQT1 males are at risk, whereas most LQT2 and LQT3 patients who become symptomatic experience their first symptoms around puberty and here particular females are at risk. […] The arrhythmias in LQTS originate from the last part of the ventricular action potential where severe action potential prolongation results in early afterdepolarisations that at one instant reach threshold for subsequent fast sodium inward current and a trigger beat that then degenerates into fast polymorphic ventricular arrhythmia: Torsades de Pointes and ventricular fibrillation.

• #2 Congenital long QT syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-3-18

  The delayed rectifier current (IK) is a major determinant of the phase 3 of the cardiac action potential. It comprises two independent components: one rapid (IKr) and one slow, (IKs). […] The KCNQ1 gene and the KCNE1 gene encode respectively the alpha (KvLQT1) and the (MinK) subunit of the potassium channel conducting the IKs current. KCNQ1 mutations are found in the LQT1 variant of LQTS which is also its most prevalent form. […] The KCNH2 gene and the KCNE2 gene encode respectively the alpha (HERG Human Ether-a-go-go Related Gene) and the (MIRP) subunit of the potassium channel conducting the IKr current. This is the second most common variant of LQTS accounting for 35-40% of mutations in LQTS genotyped patients. […] The SCN5A gene encodes the protein of the cardiac sodium channel. The Na+ channel protein is a relatively large molecule that folds onto itself to surround the channel pore.

• #2 Molecular pathogenesis of long QT syndrome type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5063268/

  When IKs is defective because of a KCNQ1 mutation, the ventricular repolarization or QT interval fails to shorten appropriately, thus creating a highly arrhythmogenic condition. […] The LQT1-related KCNQ1 gene is 404 kb long and located on chromosome 11p15.5. […] To date, over 250 mutations in KCNQ1 have been found to be linked to LQT1 and new LQT1 causing mutations continue to be identified. […] Importantly, these data are consistent with the results from another clinical study. […] Mutations in the transmembrane, linker, and pore region of KCNQ1 are usually defined as high-probability disease-causing mutations that tend to cause severe cardiac events in patients at younger ages compared to mutations in the COOH terminal region. […] The mutation type, specific location, and degree of dysfunction play a critical role in the clinical course of LQT1.

• #2 An Overview of Diagnosis and Management Strategies for Long QT Syndrome

  https://www.innovationsincrm.com/cardiac-rhythm-management/articles-2017/june/1046-management-strategies-for-long-qt-syndrome

  The severe arrhythmia phenotypes noted in the fetal state can be explained in part by mutations with severe biophysical phenotypes. […] The net effect of sex hormones on the expression and function of cardiac ion channels is thought to be a lower repolarization reserve in women, rendering them more prone to QTc prolongation and TdP occurrence in the presence of a LQTS-causing mutation. […] LQT1 patients are particularly vulnerable to life-threatening events during exertion, and are most responsive to β-blockers. […] LQT2 is known to be life-threatening in females of child-bearing age when compared with male counterparts of the same age. […] LQT3 events occur during times of relative bradycardia and thus may manifest during sleep. […] In high-risk patients in whom β-blockers are either not effective or not tolerated, or are used in patients who are non-compliant, there should be a strong consideration for LCSD.

• #2 Clinical and Genetic Characteristics of Long QT Syndrome – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-clinical-genetic-characteristics-long-qt-articulo-13109918

  Despite these developments, a quarter of patients do not have mutations in the genes identified to date. […] Long QT syndrome displays great genetic heterogeneity. More than 500 mutations distributed in 10 genes have been described in this condition: KCNQ1, HERG, SCN5A, KCNE1, KCNE2, ANKB, KCNJ2, CACNA1, CAV3, and SCN4B. […] Molecular genetic studies developed over the last 11 years have yielded important genotype-phenotype correlations, which have helped to guide the treatment approach. […] The characteristic ventricular arrhythmia of LQTS is known as torsade de pointes. It presents when the QT interval is prolonged, regardless of the etiology. […] The electrical and contractile phenomena that occur in the cardiomyocyte are controlled by these structures. Ion channels form macromolecular complexes consisting of a main unit that forms the channel pore and auxiliary proteins that regulate it.

• #2 Congenital long QT syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-3-18

  It was concluded that Na+ channel mutations produce the LQTS phenotype by inducing a „gain of function” leading to increase in the Na+ inward current which prolongs action potential duration. […] LQT8 is a rare variant of LQTS characterized by marked QT interval prolongation, often presenting with 2:1 functional atrioventricular block and macroscopic T wave alternans, and syndactyly. […] Molecular screening identified two missense mutation in the voltage-gated calcium channel gene (CACNA1c), in all probands analyzed, causing a reduced channel inactivation responsible for calcium overload, a well known mechanism for tissue damage and arrhythmias induction.

• #2 Long QT syndrome – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/long-qt-syndrome/symptoms-causes/syc-20352518

  Acquired long QT syndrome. This type of LQTS is caused by another health condition or medicine. It usually can be reversed when the specific cause is found and treated. […] Many genes and gene changes have been linked to long QT syndrome (LQTS). […] A medicine or other health condition can cause acquired long QT syndrome. […] If a medicine causes acquired long QT syndrome, the disorder may be called drug-induced long QT syndrome. More than 100 medicines can cause prolonged QT intervals in otherwise healthy people. […] Health conditions that can cause acquired long QT syndrome include: […] Proper medical treatment and lifestyle changes can help prevent complications of long QT syndrome.

• #2 Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation

  https://www.mdpi.com/1422-0067/22/15/8090

  Many drugs with no structural similarities (antihistamines, antipsychotics, antibiotics) share a common mechanism by which they cause diLQTS and TdP. This shared mechanism has been identified as blockade of the IKr on the cardiac action potential carried out by a voltage-gated potassium channel called Kv11.1. […] The Kv11.1 channel is a homotetramer, composed of four α-subunits all encoded by the same gene (KCNH2). […] The gating kinetics in the different states of the potassium channel have been extensively studied, indicating that Kv11.1 elicits unusual gating kinetics compared to other voltage-gated potassium channels, in that inactivation occurs at a faster rate than activation and deactivation, and is a voltage-dependent process. […] This pharmacological disruption of cardiac repolarization is widely simulated to predict drug proarrhythmic risk in preclinical stages of drug development, mainly using the ICH guidelines.

• #2 Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | AER Journal

  https://www.aerjournal.com/articles/acquired-long-qt-syndrome-and-electrophysiology-torsade-de-pointes?language_content_entity=en

  Recent studies have shown that some drugs designated as arrhythmogenic IKr blocker can generate arrhythmias by augmenting INa-L through the PI3K pathway. […] Several recent reports from this laboratory have provided strong evidence for a pathogenic role of autoimmune and inflammatory conditions in the development of QTc prolongation. […] In summary, cardiac or systemic inflammation promotes QTc-interval prolongation via cytokine-mediated effects and this may increase SCD risk. […] The susceptibility to acquired QT interval prolongation can be influenced by genetic variations. […] The overall incidence of drug-induced LQTS in a given population is difficult to estimate. […] QT prolongation is one of the most common reasons for drug withdrawal from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient.

• #2 Clinical and Genetic Characteristics of Long QT Syndrome – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-clinical-genetic-characteristics-long-qt-articulo-13109918

  Long QT syndrome (LQTS) is an arrhythmogenic ion channel disorder characterized by severely abnormal ventricular repolarization, which results in prolongation of the electrocardiographic QT interval. […] Eleven years after the identification of the principle cardiac channels involved in the condition, hundreds of mutations in, to date, 10 genes have been associated with the syndrome. […] Genetic investigations carried out up until the present have shown that, although the severe form of the disease is sporadic, there are a number of common polymorphisms in genes associated with the condition that may confer susceptibility to the development of torsade de pointes in some individuals, particularly when specific drugs are being administered. […] Understanding of the molecular processes underlying the syndrome has enabled treatment to be optimized and has led to better survival among sufferers, thereby demonstrating a key correspondence between genotype, phenotype and therapy.

• #2 Long QT Interval Syndromes – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/arrhythmogenic-cardiac-disorders/long-qt-interval-syndromes

  Prolongation of action potentials increases the probability of transmembrane voltage oscillations occurring during the depolarized myocyte action potential (early afterdepolarizations). If the action potential durations of myocytes in a local area vary, these oscillations may reactivate neighboring myocytes that have repolarized and thus create torsades de pointes ventricular tachycardia (TdeP VT). The risk of TdeP VT is dependent on the degree of QTc prolongation, particularly if it is 0.50 second. […] LQTS (particularly LQTS3) may also cause paroxysmal atrial fibrillation. […] The occurrence of TdeP VT is favored by any condition that further prolongs action potential duration, including female sex, bradycardia, hypokalemia, hypomagnesemia, and hypothyroidism. […] Long QT interval syndromes are classified based on the specific gene that has mutated.

• #2 An Overview of Diagnosis and Management Strategies for Long QT Syndrome

  https://www.innovationsincrm.com/cardiac-rhythm-management/articles-2017/june/1046-management-strategies-for-long-qt-syndrome

  Despite the well-adjudicated clinical outcomes of LQTS patients on β-blocker therapy and following an LCSD, a subset of patients remain at high risk, and thus warrant ICD implantation. […] Understanding the LQTS subtype, location of the mutation, presence or absence of a haplotype deficiency, and new information regarding whole-exome sequencing have altered the genetic landscape and inundated clinical electrophysiologists with a wealth of information.

• #2

  https://www.jci.org/articles/view/19844

  Because the functional consequences of most of the Na+ channel mutations that cause LQT-3 syndrome are subtle increases in channel activity during the action potential plateau, cellular experimental work suggested that conventional Na+ channel blockers such as mexiletine, tocainide, and lidocaine might prove useful in treating this LQTS variant. […] Thus genotype, which underlies phenotype, can dictate the most promising therapeutic approach.

• #2

  https://link.springer.com/article/10.1007/s00246-019-02151-x

  Recently, the application of a drug developed to assist with ion channel trafficking to the cell membrane in cystic fibrosis has shown promise for rescuing the phenotype of LQTS in patients with trafficking defects in hERG. […] Given the gain-of-function mutation in LQT3, it is mechanistically intuitive that sodium channel blockade would ameliorate risk of arrhythmia. […] CRISPR/Cas9 is a highly accurate and efficient genome editing technique, which is faster and cheaper than other preceding gene editing technologies. […] CRISPR/Cas9 can generate isogenic mutant lines from control iPSCs, or genetically corrected iPSCs from mutant lines, thus eliminating epigenetic differences or unknown genetic modifiers which may introduce phenotype variability in studying disease-causing mutations in LQTS.

• #2

  https://link.springer.com/article/10.1007/s00246-019-02151-x

  Other very rare LQTS variants are related to kinase activities, such as AKAP9 (LQT11), CALM1 (LQT14), and CALM2 (LQT15). […] The ECG of a patient with LQTS characteristically shows QT prolongation when measured appropriately in leads II or V5 using a correction formula for heart rate (QTc). […] QTc values correlate with risk of life-threatening arrhythmia event with a linear relationship between increasing QTc and increasing risk for all three common genotypes, LQT1, 2, and 3. […] The current standard of care therapy for LQT1, 2, and 3 includes non-cardioselective beta-blockers, preferentially nadolol, that are hypothesized to dampen down adrenergic stimulation of the heart. […] Beta-blockers are proven to reduce the occurrence of life-threatening ventricular arrhythmias and subsequent risk of sudden death in LQTS patients.

• #2

  https://link.springer.com/article/10.1007/s00246-019-02151-x

  RNA interference (RNAi)-based therapeutics may prove an effective adjunct to standard of care therapy in LQTS. […] Studies have demonstrated the potential RNAi offers for the treatment of LQTS and its ability to be patient-specific in cultured cells. […] LQTS is a rare inherited cardiac condition associated with risk of malignant ventricular arrhythmias. […] The three major subtypes of LQTS are LQT1, LQT2, and LQT3, caused by mutations in the ion channel genes KCNQ1, KCNH2, and SCN5A, respectively. […] Current standard of care therapy for LQTS is the prescription of non-cardioselective beta-blockers. […] Increasingly, a more nuanced understanding of LQTS pathophysiology is leading towards genotype-specific therapies such as the role of mexiletine for a subset of patients with LQT3.

• #2 Molecular pathogenesis of long QT syndrome type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5063268/

  The findings to date indicate that mechanisms underlying LQTS are not only multifactorial, but are also involved in pathway crosstalk. […] The loss-of-function in IKs, which is a major repolarization current, occurs due to a KCNQ1 mutation and decreases the repolarization reserve. […] However, this may be insufficient to elicit a full-blown LQT1 phenotype, especially at rest.

• #3 Long QT Interval Syndromes – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/arrhythmogenic-cardiac-disorders/long-qt-interval-syndromes

  More than 15 forms of LQTS have been described, but most cases fall into 3 subgroups: […] Long QT syndrome type 1 (LQTS1): Loss-of-function mutation of gene KCNQ1, which encodes an adrenergic-sensitive Kv7.1 channel responsible for the slow outward potassium current (IKs). […] Long QT syndrome type 2 (LQTS2): Loss-of-function mutation of gene KCNH2, which encodes the hERG channel responsible for the rapid outward potassium current (IKr). […] Long QT syndrome type 3 (LQTS3): Gain-of-function mutation of gene SCN5A, which encodes the Nav1.5 channel responsible for the inward sodium current (INa). […] The vast majority of cases are LQTS1, LQTS2, or LQTS3. These 3 forms are inherited as autosomal dominant disorders with incomplete penetrance. […] Some forms of LQTS are more associated with certain triggers than others.

• #3 Diagnosis, management and therapeutic strategies for congenital long QT syndrome | Heart

  https://heart.bmj.com/content/108/5/332

  LQTS type 3 is based on gain-of-function variants in SCN5A, the gene encoding the fast inward cardiac sodium current (I Na). […] Gain of function relates to an increased amplitude of the late sodium inward current (during the plateau phase), which will also lead to prolongation of the action potential. […] The age of onset of arrhythmias is typically younger in LQT1 patients and in particular LQT1 males are at risk, whereas most LQT2 and LQT3 patients who become symptomatic experience their first symptoms around puberty and here particular females are at risk. […] The arrhythmias in LQTS originate from the last part of the ventricular action potential where severe action potential prolongation results in early afterdepolarisations that at one instant reach threshold for subsequent fast sodium inward current and a trigger beat that then degenerates into fast polymorphic ventricular arrhythmia: Torsades de Pointes and ventricular fibrillation.

Zobacz więcej